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Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies
Author(s) -
Cagliani Rachele,
Magri Francesca,
Toscano Antonio,
Merlini Luciano,
Fortunato Francesco,
Lamperti Costanza,
Rodolico Carmelo,
Prelle Alessandro,
Sironi Manuela,
Aguennouz Mohammed,
Ciscato Patrizia,
Uncini Antonino,
Moggio Maurizio,
Bresolin Nereo,
Comi Giacomo P.
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9364
Subject(s) - dysferlin , muscular dystrophy , biology , sarcolemma , myopathy , phenotype , limb girdle muscular dystrophy , emerin , annexin , mutation , muscle disorder , dystrophin , medicine , pathology , endocrinology , genetics , skeletal muscle , gene , staining , nuclear protein , transcription factor
Mutations in the DYSF gene underlie two main muscle diseases: Limb Girdle Muscular Dystrophy (LGMD) 2B and Miyoshi myopathy (MM). Dysferlin is involved in muscle membrane‐repair and is thought to interact with other dysferlin molecules and annexins A1 and A2 at the sarcolemma. We performed genotype/phenotype correlations in a large cohort of dysferlinopathic patients and explored the possible role of annexins as modifier factors in LGMD‐2B and MM. In particular, clinical examination, expression of sarcolemmal proteins and genetic analysis were performed on 27 dysferlinopathic subjects. Expression of A1 and A2 annexins was investigated in LGMD‐2B/MM subjects and in patients with other muscle disorders. We identified 24 different DYSF mutations, 10 of them being novel. We observed no clear correlation between mutation type and clinical phenotype, but MM patients were found to display muscle symptoms significantly earlier in life than LGMD subjects. Remarkably, dysferlinopathic patients and subjects suffering from other muscular disorders expressed higher levels of both annexins compared to controls; a significant correlation was observed between annexin expression levels and clinical severity scores. Also, annexin amounts paralleled the degree of muscle histopathologic changes. In conclusion, our data indicate that the pathogenesis of different inherited and acquired muscle disorders involves annexin overexpression, probably because these proteins actively participate in the plasmalemma repair process. The positive correlation between annexin A1 and A2 and clinical severity, as well as muscle histopathology, suggests that their level may be a prognostic indicator of disease. © 2005 Wiley‐Liss, Inc.